This invention relates to cyanoacrylate compositions useful as medical devices.
Cyanoacrylate tissue adhesives have been in clinical endovascular use since the 1970""s. Liquid acrylics are extremely useful as endovascular embolic agents because of their ability to create permanent vascular occlusion. They may, however, be difficult to use technically as they have a variable and sometime unpredictable polymerization time based on the operator selection of an acrylic mix with either iodinated oil or glacial acetic acid. The appropriate choice of polymerization time depends on a number of variables, including the transit time between arterial and venous elements in the embolic target, the target volume, the architecture of the target, for example, a fistula versus nidus, which affects the relative endovascular turbulence, and the method of injection (bolus, full column, or wedge-flow arrest). Typical complications associated with the use of liquid acrylics for embolization occur when there is occlusion of normal arterial branches or acrylic penetration into critical venous outflow channels. Additionally, reflux of acrylic around the delivery catheter tip can result in permanent endovascular catheter adhesion, which may require permanent catheter implantation. Overzealous attempts at withdrawal can produce catheter fracture (and resultant embolization of flow-directable distal catheter segment), vascular damage with resultant dissection/occlusion, or avulsion of the involved vascular pedicle (with resultant subarachnoid hemorrhage).
Alkyl alpha cyanoacrylates are a homologous series of organic molecules which polymerize and can adhere to moist living tissues. The methyl homolog has been used in homeostasis and non-suture closure since 1960, but its histoxicity severely limited its clinical usefulness. The synthesis of longer alkyl chain homologs and the evaluation of these in various animal species have shown that the histoxicity of cyanoacrylates could be diminished without sacrificing their hemostatic and tissue bonding properties. Extensive animal studies have been completed using n-butyl and isobutyl homologs, and preliminary human trials have been undertaken.
Polymerization speed is another function of chain length. It has been reported that homologs with six or more carbon atoms on the alkyl chain polymerize almost immediately upon contact with moist tissues. The n-butyl and isobutyl monomers require from four to 15 seconds, while the methyl homolog remains as a monomer for 30 to 55 seconds. The ability to wet and spread easily over the surface of an anticoagulated blood film is common to homologs with alkyl chains containing four or more carbon atoms. The ethyl and propyl derivatives wet and spread poorly, and the methyl not at all.
Since the advent of NBCA (n-butyl-2-cyanoacrylate), there has been very little advancement in the science of xe2x80x9csupergluexe2x80x9d embolization of vascular structures, primarily arteriovenous malformations (AVMs). Certain properties of superglue are advantageous for embolization, such as adhesion, the ability transform from a liquid or solid state and rapid polymerization. However, these properties can be detrimental when present to an excessive degree, in particular, adhesion which can result in permanent catheter fixation. Rapid polymerization allows the material to set in flowing blood without passing through small channels into venous structures. However, rapid polymerization may also release amounts of heat that can cause damage to the surrounding tissue, for example, brain tissue.
Hydrophilic catheter coatings have been developed in the hope of reducing the risk of inadvertent endovascular catheter fixation during embolization due to reduced bond strength between the hydrophilicly coated catheter and the adhesive. However, micro catheter cyanoacrylate adhesion remains a problem during intravascular embolization. Inadvertent gluing of the catheter tip onto the artery is a well recognized and distressing complication. Vessel rupture or occlusive embolization of a detached catheter tip may occur if excessive force is used to attempt to retrieve the catheter. Fortunately, permanent intra vascular catheter fixation is usually well tolerated, nonetheless this remains a highly undesirable event. An in vitro study has shown that recently available hydrophilic micro catheter coatings decrease catheter adhesion of both pure normal butyl cyanoacrylate and mixtures of normal butyl cyanoacrylate and ethiodized oil. Although hydrophilicly coated catheters have the potential of decreasing the occurrence of inadvertent endovascular catheter fixation, the level of operator proficiency and experience, and perhaps most importantly, the actual adhesive composition that is used stills play a major role in these events.
There exists a continuing unmet need for a composition that has the correct amount of cohesiveness, produces a robust rubbery casting, is tolerated by the body, can trigger the appropriate amount of tissue inflammation response and is radiopaque.
It has now been surprisingly found that such a composition exists that has the requisite combination of properties in cohesion, stability, body tolerance, low catheter adhesion and radiopacity.
A composition comprising of a monomer component comprised of at least one alkyl cyanoacrylate and at least one inhibitor, and a second component comprised of a resultant aggregate structure formed from an alkyl cyanoacrylate monomer, an alkyl esterified fatty acid and an opacificant agent where said composition forms a resultant aggregate structure when said composition contacts an anionic environment. The compositions are useful for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass in an anionic environment. The composition are also useful for ablating diseased or undesired tissue by cutting off the blood supply to the tissue.
No drawings are included.
The present invention provides a composition comprising of a monomer component comprised of at least one alkyl cyanoacrylate, at least one inhibitor and a second component that functions as a opacificant agent and polymerization retardant. The composition is useful for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass (xe2x80x9ca spacexe2x80x9d). In particular, the composition is useful for filling an existing space, e.g., the lumen of a blood vessel, or the sac of an aneurysm, a space created by a transiently placed external device, e.g., a catheter or like device, a space created by a procedure, e.g., an excision or like procedure or implantation of an object, e.g., a stent or like device, or a space created by the composition; the composition is also useful for adhering tissue to tissue, or adhering tissue to a device. The composition has the property of polymerizing when it comes in contact with an anionic environment, or when it is deployed in situ in an existing space, e.g., the lumen of a blood vessel, or the sac of an aneurysm, a space created by a transiently placed external device, e.g., a catheter or like device, a space created by a procedure, e.g., an excision or like procedure or implantation of an object, e.g., a stent or like device, or a space created by the composition;
Another aspect of the present embodiment is where the second component is comprised of a halogenated oil. Preferred are iodinated and brominated oils, such as Ethiodol, Lipiodol and Pantopaque. Most preferred is Ethiodol.
One embodiment of the present invention is where the second component is Ethiodol.
Another aspect of the present embodiment is where the second component is comprised of a resultant aggregate structure, i.e., an oligomer or polymer, formed from a composition of alkyl cyanoacrylate monomer, an alkyl esterified fatty acid and an opacificant agent.
Another aspect of the present embodiment is where the monomer component is comprised of one alkyl cyanoacrylate monomers, and at least one inhibitor. A preferred aspect is where the monomer component is comprised of 2-hexyl cyanoacrylate and one inhibitor. An especially preferred aspect is where the monomer component is comprised of 2-hexyl cyanoacrylate, and three inhibitors, most especially preferred is the aspect where the inhibitors are hydroquinone, p-methoxyphenol and phosphoric acid. An especially preferred embodiment of the present invention is a composition comprised of the present monomer component, and a second component comprising of a resultant aggregate structure, i.e., an oligomer or polymer, formed from 2-hexyl cyanoacrylate monomer, an alkyl esterified fatty acid and an opacificant agent, most especially preferred is where the alkyl esterified fatty acid is ethyl myristate and the opacificant agent is gold.
Another aspect of the present embodiment is where the monomer component is comprised of two or more different alkyl cyanoacrylate monomers, and at least one inhibitor. A preferred aspect is where the monomer component is comprised of methyl cyanoacrylate, n-hexyl cyanoacrylate and at least one inhibitor. An especially preferred aspect is where the monomer component is comprised of methyl cyanoacrylate, n-hexyl cyanoacrylate and at least three inhibitors, a most especially preferred aspect is where the inhibitors are hydroquinone, p-methoxyphenol and acetic acid. A particularly preferred embodiment of the present invention is the composition comprised of the present monomer component, and a second component comprising of the resultant aggregate structure, i.e., an oligomer or polymer, formed from n-hexyl cyanoacrylate monomer, an alkyl esterified fatty acid and an opacificant agent, most preferred is where the alkyl esterified fatty acid is ethyl myristate and the opacificant agent is gold.
Another embodiment of the present invention is a method for purifying alkyl cyanoacrylate monomer to its crystalline form. In particular, a method of purifying an alkyl cyanoacrylate to about 95% purity or better, preferred is to about 97% purity or better, most preferred is to about 98% purity or better, and most especially preferred is to about 99% purity or better.
Another embodiment of the present invention is a substantially pure alkyl cyanoacrylate monomer. In particular, methyl cyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-hexyl cyanoacrylate, 2-hexyl cyanoacrylate and 2-octyl cyanoacrylate, purified to about 95% purity or better, preferred is to about 97% purity or better, most preferred is to about 98% purity or better, and most especially preferred is to about 99% purity or better. A particularly advantageous aspect of the present invention is where the alkyl cyanoacrylate monomer is isolated in its crystalline form.
It is known to those of ordinary skill in the art that the predictability of polymerization properties of alkyl cyanoacrylate monomers is related to the purity of the monomer that are used. These polymerization properties, include but are not limited to rate of polymerization, and stability of the monomer during storage. Another advantage of substantially pure alkyl cyanoacrylates is that compositions incorporating substantially pure alkyl cyanoacrylates require smaller amounts of additives, e.g., inhibitors, stabilizers and the like, to obtain a desired result that would otherwise have require greater amounts of the same additive. An immediate benefit of this advantage is in cost savings from being able to use less material. Another benefit, is that the composition will quantitatively have lower amounts of additives. This is a desirable outcome for any composition that is subject to regulatory approval by the U.S. Food and Drug Administration, or like agency, prior to marketing. The current embodiment provides alkyl cyanoacrylate monomers whose rates of polymerization can be predicted, and where the un-reacted monomer (xe2x80x9cpre-polymerxe2x80x9d) compositions are more stable. The properties provide beneficial advantages for the use of the compositions of the present invention because by being able to predict the polymerization characteristics of a monomer, one of ordinary skill in the art can select the monomer with the appropriate polymerization properties for a desired use, or to formulate monomer compositions having desired polymerization properties. Prior to the present invention, alkyl cyanoacrylates have not been available in substantially pure form because they are difficult to purify using conventional chemical methodology. Moreover, most of these methodologies involve conditions that cause the alkyl cyanoacrylate to degrade or to spontaneously polymerize. Therefore before the present invention, the benefits of substantially pure alkyl cyanoacrylate monomers were not available.
Another embodiment of the present invention provides a method for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass by administering a composition of the present invention with an administering means, comprising a means for stabilizing fluid flow distal or proximal to the body space being treated, and a means for delivering said composition to the desired body space. An embodiment of said administering means is where said means for stabilizing fluid flow distal or proximal to the body space being treated is in a first device, and said means for delivering said composition to the desired body space is in a second device. An embodiment of said first device comprises a temporary inflatable balloon, or like structure, that is inflated to stabilize fluid flow distal or proximal to the body space to be treated, and deflated for removal after some period after the composition has been delivered. Optionally said balloon structure may be juxtaposed adjacent to the body space where said composition is deposited, and inflated such that said balloon structure maintains said composition at the body space while the composition is polymerizing, and deflated for removal after some period after the composition has been delivered. An embodiment of the said second device comprises a catheter, or like device for delivering and depositing the composition of the present invention at a desired location. Another embodiment of said administering means is where said means for stabilizing fluid flow distal or proximal to the body space being treated, and said means for delivering said composition to the desired body space are within a single device or apparatus.
The types of unfilled volumes or spaces within the scope of the present invention includes, but are not limited to the following instances.
For example, one aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding an existing space, such as, a lumen of a passageway in the body, e.g., a blood vessel, a duct, an aneurysm, or a fistula. Examples of the types treatments covered by this method of use, include but are not limited to the following. The present invention is useful as a method of treating arteriovenous malformations (AVM) where the blood vessel(s) that feed the AVM are occluded thereby cutting off the blood supply to the AVM. The present invention is useful as a method to ablate diseased or undesired tissue by cutting off the tissue""s blood supply. In particular, the present invention is useful as a method of treating a tumor having a discrete blood supply, where the blood vessel(s) that feed the tumor are occluded thereby cutting off the blood supply to the tumor resulting in diminished growth or death of the tumor. The present invention is useful as a method of preventing or mitigating the development of an aneurysm by creating a partial occlusion at a location in the blood vessel selected to modify the fluid dynamics within the vessel to mitigate the formation or development of an aneurysm. The present invention is useful.as a non-surgical method of treating symptomatic uterine leiomyomas by embolizing/occiuding the uterine artery. This method has been reported using a non alkyl cyanoacrylate composition in Journal of Vascular and Intervention Radiology, 10:891-894, July-August 1999. The present invention is useful as a method of sterilizing a female mammal by occluding the fallopian tubes thereby preventing the passage of the eggs from the ovaries to the uterus. The use of an occluding agent to sterilize a female mammal is disclosed in U.S. Pat. No. 5,989,580 xe2x80x9cMethod of Sterilizing Female Mammals,xe2x80x9d herein incorporated by reference. The methods disclosed in this patent can be advantageously applied using the compositions of the present invention, and are within the scope of the present invention. The present invention is useful for obliterating the left atrial appendage. The left atrial appendage is derived from the left wall of the primary atrium. It has been observed that patients with atrial fibrillation have a predilection for thrombus to form in the left atrial appendage. A review of this condition and the current status of treatment is disclosed in the article, xe2x80x9cLeft Atrial Appendage: structure, function, and role in thromboembolismxe2x80x9d N. M. Al-Saady, et. al. The present invention provides an advantageous method of obliterating the left atrial appendage.
Another aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding a space created by a transiently placed external device, such as, a catheter balloon, a space created by a transiently placed external device, e.g., a catheter or like device. Examples of the types of treatments covered by this method of use include, but are not limited to the following. The present invention is useful as a method of treating an aneurysm by filling the space within the aneurysm with a composition of the present invention, where the composition polymerizes in the space within the aneurysm, thereby preventing the rupture of the aneurysm. The present method of treatment can be practiced using an administering means, comprising a means for stabilizing fluid flow distal or proximal to the body space being treated, and a means for delivering said composition to the desired body space. An embodiment of said administering means is where said means for stabilizing fluid flow distal or proximal to the body space being treated is in a first device, and said means for delivering said composition to the desired body space is in a second device. An embodiment of said first device comprises a temporary inflatable balloon, or like structure, that is inflated to stabilize fluid flow distal or proximal to the body space to be treated, and deflated for removal after some period after the composition has been delivered. Optionally said balloon structure may be juxtaposed adjacent to the body space where said composition is deposited, and inflated such that said balloon structure maintains said composition at the body space while the composition is polymerizing, and deflated for removal after some period after the composition has been delivered. An embodiment of the said second device comprises a catheter, or like device for delivering and depositing the composition of the present invention at a desired location. Another embodiment of said administering means is where said means for stabilizing fluid flow distal or proximal to the body space being treated, and said means for delivering said composition to the desired body space are within a single device or apparatus. Such apparatuses include, but are not limited to, catheters, catheter coils, catheter wires, catheter balloons, or like devices. Many examples of such devices are known to those of ordinary skill in the art. For example, U.S. Pat. No. 5,795,331 xe2x80x9cBalloon Catheter For Occluding Aneurysms of Branched Vesselsxe2x80x9d, incorporated herein by reference, discloses a device and methods for delivering compositions, such as those of the present invention. The device described combines an inflatable balloon with a catheter as a single apparatus, where the balloon is distal or proximal to the opening of the catheter. Embodiments of the described apparatus are commercially available from Micro Therapeutics, Inc., 2 Goodyear, Irvine, Calif. 92618, as a line of medical devices, such as, the Rebar(trademark) Micro Catheter, Equinox(trademark) Occlusion Balloon System and SilverSpeed(trademark) guidewires. Of additional note is that devices under the Rebar(trademark) Micro Catheter line have been approved by the U.S. Food and Drug Administration for use in treating conditions such as those within the present invention. U.S. Pat. No. 5,882,334 xe2x80x9cBalloon/Delivery Catheter Assembly With Adjustable Balloon Positioning,xe2x80x9d incorporated herein by reference, assigned to Target Therapeutics, San Jose, Calif., and U.S. Pat. No. 6,015,424 xe2x80x9cApparatus and Method For Vascular Embolizationxe2x80x9d, incorporated herein by reference, assigned to MicroVention, Inc., Aliso Viejo, Calif., describe like devices that can be employed in practicing the present invention. Additional commercial sources for like devices, include but are not limited to the following corporations, Guidant, Inc., Indianapolis, Ind.; Cook Incorporated, Bloomington, Ind.; Cordis, a subsidiary of Johnson and Johnson; and the SciMed, Target Therapeutics, and Medi-tech Divisions Boston Scientific Corporation. The present invention has been practiced following the procedure and utilizing like devices described in Neurosurgery, Vol. 31, No. 3, September 1992, page 591 xe2x80x9cCarotid-Cavernous Fistula Caused by a Ruptured Intra-cavernous Aneurysm: Endovascular Treatment by Electrothrombosis with Detailable Coils.xe2x80x9d The reference describes a procedure using a temporary inflatable balloon catheter, and a catheter for placement of a detachable platinum coil. A temporary balloon occlusion is performed proximally to a fistula, and then followed by the insertion of a platinum detachable coil into the fistula. The temporary balloon occlusion stabilizes the immediate environment near the fistula from the disturbed flow, increased flow, turbulence, or combination thereof, created by normal unrestricted blood flow, while a thrombus forms around the platinum wire. In the present invention, a temporary balloon occlusion performs a similar function of stabilizing the immediate environment near the body space to be treated, for example, a fistula or aneurysm, from the disturbed flow, increased flow, turbulence, or combination thereof created by normal unrestricted blood flow. The temporary balloon, optionally, may also be used to temporarily form a seal at the opening of the body space, while the composition that had been deposited in the body space is polymerizing to its final form. After a period of time sufficient for the polymerization to be completed, the temporary balloon catheter is deflated and withdrawn.
Another aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding a space created or resulting from a procedure, such as with the excision of tissue, or insufflation. Examples of the types of treatments covered by this method of use include, but are not limited to the following. The present invention is useful as a method of treating or mitigating capillary oozing.
Another aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding a space created by the placement or implantation of an object, such as, a medical device. Examples of the types of uses covered by this method of use include, but are not limited to the following. The present invention is useful as a method of restoring the normal fluid dynamics at the peripheral edges of a vascular stent by filling the dead spaces between the stent and the lumen wall created by the implantation of the stent.
Another aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding a space created by the composition itself, such as, where the composition is used as a bulking agent. Examples of the types of uses covered by this method of use include, but are not limited to the following. For example, a method of recreating the normal contours to skin following an adverse event, such as, physical trauma.
Another embodiment of the present invention provides a method of affixing therapeutics, chemotherapeutics, radiation delivery devices, gene therapy compositions to a desired location where the active agents can be advantageously maintained in proximity to the desired location. The active agent is then release gradually as the resultant aggregate structure from the composition of the present invention is biodegraded. Alternatively, the composition of the present invention can be modified to allow for a specific rate of delivery. This use is particularly beneficial in the treatment of tumors that are ideally treated by localized dosages of chemotherapy or radiation. An advantage of this method is that the patient would not be subjected to as large of a dose of the therapeutic or radiation as would be necessary, if the therapeutic or radiation was administered on a systemic basis. Another advantageous use the present invention is for the delivery of DNA compositions used in gene therapy. A long standing problem in the gene therapy arts has been the inability of practitioners to deliver the DNA therapeutic to the locales in the body most ideally suited for the treatment. The present invention provides a method of affixing the DNA composition at a desired site, where the active agent is then slowly released over a period time as the composition of the present invention biodegrades. Alternatively, a composition of the present invention can be modified to release the active agent in a controlled delivery manner.
Another embodiment of the present invention provides a method of utilizing magnetically controlled particles embedded in a composition of the present invention to deploy the composition to a desired location, xe2x80x9cMagnetic Probe for the Stereotaxic Thrombosis of Intracranial Aneurysms,xe2x80x9d Alksne, J. F., et. al, Journal of Neurology, Neurosurgery and Psychiatry, April 1967, 30(2):159-62; xe2x80x9cMagnetically Controlled Focal Intravascular Thrombosis in Dogsxe2x80x9d Alksne, J. F., et. al, Journal of Neurosurgery, November 1966, 25(5):516-25; xe2x80x9cThrombosis of Intracranial Aneurysmsxe2x80x94An experimental approach utilizing magnetically controlled iron particlesxe2x80x9d Alksne, J. F., et. al, Radiology February 1966. 86(2):342-3
Another embodiment of the present invention provides a method of adhering, joining, connecting or affixing a first section of tissue to a second section of tissue. Examples of the types of uses covered by this method of use include, but are not limited to the following. The present invention is useful as a method of adhering, joining, or connecting two blood vessels, e.g., anastomoses, where blood vessels are quickly and efficiently adhered, joined or connected, under surgical conditions without the use of sutures or staples. The present invention is useful as a method of treating primary wounds or wounds that require immediate intervention, such as, trauma wounds, where the compositions of the present invention are used to temporarily close the wound to minimize the lost of fluids due to evaporation, and to mitigate infection.
Another embodiment.of the present invention provides a method of adhering, joining, connecting, or affixing tissue to a non-tissue surface, such as a medical device. Examples of the types of uses covered by this method of use include, but are not limited to the following. The present invention is useful as a method of implanting or securing venous valves, replacement heart valves, or stents at their desired location.
The aforementioned uses are possible because the compositions of the present invention remain in a controllable state for a period of time in excess of 1 second after being deployed from an administration device. This property allows the practitioner to incremental maneuver the deployment of the composition to its most ideal location, even though the composition had been partially deployed distal to the deployment device.
For instance, the compositions of the present invention have adequate cohesion to maintain its continuity once it is outside of the deployment device. Without adequate cohesion the composition would break into smaller aggregates dispersing into the blood flow.
For instance, the compositions of the present invention have appropriate adhesion properties so that when desired a deployed composition adheres to the immediate location where it is deployed so that the resultant aggregate of the monomer is placed where it is desired.
The compositions of the present invention have polymerization rate, such that, the practitioner can effect the desired amount of penetration of the composition into a particular type of space. A composition that polymerizes too quickly would hinder penetration, conversely a composition that polymerizes too slowly would make it difficult to precisely place the polymerized composition resultant aggregate of the monomer.
Another embodiment of the present invention provides a method for selectively creating an embolic blockage in the lumen of a blood vessel, duct, fistula or other like body passageways.
Another embodiment of the present invention provides a method of treating arteriovenous malformation (AVM)
As used herein the terms xe2x80x9cadhesionxe2x80x9d or xe2x80x9cadhesivexe2x80x9d means the characteristic or tendency of a material to be attracted to the surface of a second material. Adhesion occurs as the result of interactions between two materials. Depending on the characteristics of the second material relative to the first material, adhesion may or may not occur. For a single material, e.g., the composition of the present invention, the presence of adhesion is demonstrated by a material sticking to the wall of a lumen of blood vessel, i.e., there is adhesion between the material and the lumen wall. Conversely, the absence of adhesion is demonstrated for the same material where a micro-catheter tip used to deposit the material can be removed from the material, i.e., there is little adhesion between the material and micro-catheter tip.
As used herein the term xe2x80x9calkylxe2x80x9d refers to a carbon chain of one to sixteen carbon atoms, where the carbon atoms can be linear or branched.
As used herein the term xe2x80x9canionic environmentxe2x80x9d or xe2x80x9can-ionic environmentxe2x80x9d refers to an environment that is non-ionic. This an environment that is devoid of charged ions, or where the charged ions are complexed with other molecules which effectively neutralize their charge. For example, a solution of water and a sugar, such as, dextrose, and blood, is an anionic environment.
As used herein the term xe2x80x9clower-alkylxe2x80x9d refers to a carbon chain of one to eight carbon atoms, where the carbon atoms can be linear or branched. Examples of lower-alkyl moieties include but are not limited to methyl, ethyl, n-butyl, isobutyl, pentyl, n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl and 2-octyl.
As used herein the term xe2x80x9cbranched alkylxe2x80x9d refers to a carbon chain of one to sixteen carbon atoms where the carbon chain contains at least one secondary or tertiary substituted carbon atom.
As used herein the term xe2x80x9cbranched lower-alkylxe2x80x9d refers to a carbon chain of one to eight carbon atoms where the carbon chain contains at least one secondary or tertiary substituted carbon atom, for example, 2-hexyl, isobutyl, 2-heptyl and 2-octyl.
As used herein the term xe2x80x9ccohesionxe2x80x9d or xe2x80x9ccohesivexe2x80x9d means the characteristic or tendency of a material to stick together to itself. For example, this characteristic is demonstrated by a material or composition remaining intact as a single mass when introduced into a stationary fluid, or a fluid stream in motion, such as, blood. Lack of cohesive integrity results in the composition breaking up into multiple smaller subunits.
As used herein the term xe2x80x9cembolic agentxe2x80x9d refers to a non-naturally occurring composition introduced into a body cavity or the lumen of a blood vessel, duct, fistula or other like body passageways for the purpose of forming an embolic block.
As used herein the term xe2x80x9cembolic blockxe2x80x9d or xe2x80x9cembolic blockagexe2x80x9d or occlusion refers to the end result from the administration of a composition useful as an embolic agent. The resulting embolic block mechanically blocks, totally or partially, the lumen of a blood vessel, duct, fistula or other like body passageways; or in a like manner forms an occlusion within a cavity, such as an aneurysm.
As used herein the term xe2x80x9calkyl cyanoacrylate monomerxe2x80x9d refers to the chemical entity of the general structure H2Cxe2x95x90C(CN)xe2x80x94C(O)Oxe2x80x94R, where R is an alkyl moiety of one to sixteen carbon atoms, linear or branched, saturated or unsaturated, having the physical characteristic of being able to form the corresponding alkyl cyanoacrylate.
As used herein the term xe2x80x9calkyl cyanoacrylate polymerxe2x80x9d means an oligomer or polymer resulting from the polymerization of a alkyl cyanoacrylate monomer.
As used herein the term xe2x80x9calkyl esterified fatty acidxe2x80x9d means a fatty acid derivatized to form an ester functional group with a alkyl moiety, such as ethyl myristate. These compounds are formed with an alkyl moiety, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl; and carboxylic acids with alkyl side chains ranging from 1 carbon, i.e., acetic acid, through to and including 17 carbons atoms in length, such as, proprionic, butyric, isobutyric, valeric, isovaleric, pivalic, lauric, myristic, palmitic and stearic acids.
As used herein the term xe2x80x9copacificant agentxe2x80x9d is compound or composition which selectively absorbs or deflects radiation making the material visible under x-ray, or any like imaging technique. Typically such agents include, iodinated oils, and brominated oils, as well as commercially available compositions, such as Pantopaque, Lipiodol and Ethiodol. These commercially available compositions acts as opacificant agents, and also dilute the amount of liquid monomer thereby slowing the rate of polymerization. In addition certain metals, such as, gold, platinum, tantalum, titanium, tungsten and barium sulfate and the like, have properties enabling them to act as opacificant agents.
As used herein the term xe2x80x9cpolymerizationxe2x80x9d refers to the chemical process where identical monomer units react chemically to form larger aggregates of said monomeric units as oligomers or polymers.
As used herein the term xe2x80x9cpolymerization retardantxe2x80x9d means an agent that can stop or slow down the rate of polymerization. Examples of such agents are pure phosphoric acid, and 85% phosphoric acid. Certain opacificant agents, such as Pantopaque, Lipiodol and Ethiodol can also function as a polymerization retardant by diluting the amount of liquid monomer and hence slowing polymerization rate.
As used herein the terms xe2x80x9ca spacexe2x80x9d and xe2x80x9ca body spacexe2x80x9d refer to an unfilled volume or cavity in a mass. Examples of such spaces, include but are not limited by the following, an existing space within a mass, such as, the lumen of a blood vessel, the sac of an aneurysm; a space created by a transiently placed external device, such as, a catheter or like device; a space created by a procedure, such as, an excision or like procedure; a space created by implantation of an object, such as, a stent or like device; or a space created by the composition.
As used herein the term xe2x80x9cstabilityxe2x80x9d refers to the ability of a monomer component to resist degradation or polymerization after preparation but prior to use.
As used herein the term xe2x80x9cinhibitor agentxe2x80x9d refers to an agent which stabilizes a monomer composition by inhibiting polymerization. Within the context of the current invention, this term refers to agents that stabilize and inhibit polymerization by various mechanisms. By altering the amounts of one or more inhibitor agents, the rate of polymerization can be controlled. Inhibitor agents have different modes of activity, for example, hydroquinone acts primarily to inhibit high energy free radicals; p-methoxyphenol acts primarily to inhibit low energy free radicals; and phosphoric acid influences the rate of anionic polymerization.
As use herein the term xe2x80x9cNeuracryl Mxe2x80x9d refers to the composition comprising of a monomer component (xe2x80x9cM1xe2x80x9d) comprised of 2-hexyl cyanoacrylate, hydroquinone, p-methoxyphenol and phosphoric acid, and a second component (xe2x80x9cM2xe2x80x9d) comprising of a resultant aggregate structure formed from 2-hexyl-cyanoacrylate monomer, ethyl myristate and gold. As noted above, the term xe2x80x9cM1xe2x80x9d refers to the monomer component of Neuracryl M, and the term xe2x80x9cM2xe2x80x9d refers to the second component of Neuracryl M.
As used herein the term xe2x80x9cNeuracryl Axe2x80x9d refers to the composition comprising of a monomer component (xe2x80x9cA1xe2x80x9d) comprised of n-hexyl cyanoacrylate, methyl cyanoacrylate, hydroquinone, p-methoxyphenol and acetic acid, and a second component (xe2x80x9cA2xe2x80x9d) comprising of a resultant aggregate structure formed from n-hexyl cyanoacrylate monomer, ethyl myristate and gold. The term xe2x80x9cA1xe2x80x9d refers to the monomer component of Neuracryl A, and the term xe2x80x9cA2xe2x80x9d refers to the second component of Neuracryl A.
As used herein the term xe2x80x9cdeployment devicexe2x80x9d refers a device used to deploy compositions, such as, those of the present invention. Examples of such devices, include but are not limited to the following. Micro Therapeutics, Inc., 2 Goodyear, Irvine, Calif. 92618, markets medical devices, such as, the Rebar(trademark) Micro Catheter, Equinox(trademark) Occlusion Balloon System and SilverSpeed(trademark) guidewires, that are used in conjunction for treating conditions such as those within the present invention. The devices disclosed in U.S. Pat. No. 5,882,334 xe2x80x9cBalloon/delivery Catheter Assembly with Adjustable Balloon Positioning,xe2x80x9d incorporated herein by reference, is directed to a catheter assembly for delivering compositions.
The compound 2-hexyl cyanoacetate is depicted as follows, and also as Formula 3 in Schemes A and B. 
The compound 2-hexyl cyanoacrylate is depicted as follows, and also as Formula 5 in Scheme B. 
The present invention is a composition formed from alkyl cyanoacrylate monomeric units, such as, methyl, n-butyl, isobutyl, n-hexyl and 2-hexyl cyanoacrylate with at least one inhibitor agent, such as hydroquinone, p-methoxyphenol and phosphoric acid. The composition forms into its resultant aggregate structure, i.e., an oligomer or polymer, when it comes in contact with an anionic environment, such as, blood or tissue. The resultant aggregate composition has characteristics which makes it particularly well suited as an embolic agent.
The composition of the present invention possess the following properties, which are desirable in an embolization agent.
1) The composition can be prepared and maintained as a monomeric component and second component until needed.
2) The composition has the ability to reliably and predictably change from a liquid state to a solid state, which is essential for its introduction and controlled placement into the lumen of vessel, duct, fistula or other like body passageways.
3) The composition has low viscosity, which is essential for its administration by syringes and micro-catheters or other like devices.
4) The composition has cohesive characteristics such that when the composition in administered into an anionic fluid environment, such as blood, the composition forms a single aggregate structure.
5) The composition has adhesive characteristic such that it attaches to the lumen of vessel, duct, fistula or other like body passageways, but not to the degree where the device depositing the composition will become fixed to it before the practitioner can remove it.
6) The composition causes mild tissue inflammation, sufficient to cause scarring, but not so severe to cause the formation of pus. Scar formation is necessary to maintain the functionality of the embolic block after the composition has biodegraded, or otherwise eliminated from the lumen.
7) The composition is sufficiently stable to biodegradation to allow for scarring to occur.
8) The composition is radiopaque. Although not necessary for its function as an embolic agent, radiopacity allows the embolic block to be observed with x-ray or other such imaging techniques.
9) The rate of heat released during polymerization of the composition is low enough such that the heat does not adversely effect surrounding tissues that may be heat sensitive, such as brain tissue.
10) The composition and its biodegradation products are sufficiently non-histotoxic and non-cytotoxic so that its presence is well tolerated in the body.
The composition of the present invention is used by combining the monomer component and second component. Upon mixing of the components, the invention is administered into the lumen of a blood vessel, duct, fistula or other like body passageways. The characteristics of the present invention permit its accurate placement in the lumen. Contact with an anionic environment, such as blood, or tissue causes the composition to polymerize. The size of the resultant embolic block formed is determined by the amount of composition administered.
The characteristics of the composition of the invention can be modified for a specific purpose or environment for which the embolic agent is intended to be utilized. For example, changes in the length and isomeric configuration of the alkyl side chains can alter the brittleness of the resultant aggregate of cyanoacrylate monomers. Alkyl chains that result in the formation of smaller aggregates tend to be less brittle, while larger aggregates tend to be less flexible. In addition, by combining monomers with different alkyl side chains the characteristics of the resultant polymer can be modified to what is optimal for a desired application.
Cyanoacrylates generate heat as they change from monomeric to polymeric form. The amount and rate of heat released, if excessive, can have a detrimental effect on the living tissue proximate to the vessel. Control of the amount and rate at which heat is release during polymerization is critical to the utility of composition.
The monomer component of the present invention is prepared by forming the desired precursor ester from the corresponding alkyl alcohol and cyanoacetic acid resulting in the desired alkyl cyanoacetate as depicted in Scheme A. The starting materials for this reaction are commercially available, for example from Aldrich Chemical Company, Sigma Chemical Company or Fluka Chemical Company, or can be prepared following procedures known to those of ordinary skill in the art. 
The compound of Formula 2 can be any alkyl alcohol, where R is from one to sixteen carbons, including but not limited to alcohols based on alkyl groups, such as, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, heptyl, octyl, nonyl, deca, undeca, dodeca, trideca, tetradeca, pentadeca and hexadeca, where the preceding moieties are linear (e.g., n-propyl, n-butyl, n-pentyl) or variously branched, such as sec-butyl, iso-butyl, tert-butyl, iso-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-heptyl, 2-octyl and the like. Particularly advantageous alcohols are those disclosed in U.S. Pat. No. 3,728,375 entitled xe2x80x9cCyanoacrylate Adhesive Compositionsxe2x80x9d, which is hereby incorporated by reference. Especially preferred are methyl, n-butyl, iso-butyl, n-hexyl and 2-hexyl alcohols.
About 1 molar equivalents of the compounds of Formula 1 and Formula 2 are combined in a solvent like toluene at about 100 ml/molar equivalents. To this mixture is added a catalytic amount (about 1.0xc3x9710xe2x88x924 molar equivalents) of p-toluene sulfonic acid. The mixture is stirred and heated to reflux. The preparation ideally yields the desired alkyl cyanoacetate at a purity level of about 95%. The experimental conditions can be readily modified by one of ordinary skill in the art without deviating from the present invention. Aspects such as, solvent selection, reaction time, temperature and choice of reagents are well within the skill of one of ordinary skill in the art. If necessary, the material can be further purified using multiple distillations and purification techniques and procedures known to those of ordinary skill in the art, such as water extraction, vacuum distillation, column chromatography, and the like.
The desired alkyl cyanoacrylate monomer component of the present invention is synthesized from the alkyl cyanoacetate by reacting the it in a Knxc3x6evengel type reaction as depicted in Scheme B. 
About 1 molar equivalents of formaldehyde (Formula 4), which is prepared from paraformaldehyde, and piperidine (at about 0.33 ml/molar equivalents) are combined in a solvent, such as methanol (at about 166 ml/molar equivalents). To this mixture is added about 1 molar equivalents of previously prepared alkyl cyanoacetate (Formula 3) in a dropwise manner. The reaction mixture is refluxed with stirring yielding the desired alkyl cyanoacrylate polymer (Formula 5). The reaction mixture is further processed with about 0.2 to 0.7 molar equivalents, preferably about 0.2 to 0.6 molar equivalents of phosphorous pentoxide yielding the desired alkyl cyanoacrylate. Care must be taken during purification steps to prevent the compound of Formula 5 from polymerizing. To this end the system is treated with trace amounts of sulfur dioxide, and receiver flasks are treated with hydroquinone and 85% phosphoric acid. After initial purification, the desired alkyl cyanoacrylate is further purified using multiple distillations, or other purification techniques known to those of ordinary skill in the art, such as, vacuum distillation, spinning band column, and the like.
The alkyl cyanoacrylate monomer compositions of the present invention can be purified using the zone melting technique to a point where under the correct conditions it is possible to form pure crystals of the alkyl cyanoacrylate monomers, such as, methyl cyanoacrylate, -butyl cyanoacrylate, iso-butyl cyanoacrylate, n-hexyl cyanoacrylate, and 2-hexyl cyanoacrylate.
The composition is placed in a container fitted with an exchange apparatus, which will permit the differential removal of liquid impurities from the composition. The pressure of the container with the composition is reduced to about 1.5 to 0.5 Torr, preferably about 1 Torr, at the same time the temperature of the composition is reduced to about xe2x88x9228 to xe2x88x928xc2x0 C., preferably about xe2x88x9223 to xe2x88x9213xc2x0 C., most preferably about xe2x88x9217.5 to xe2x88x9218.5xc2x0 C. The composition is allowed to equilibrate at this temperature for a period of about 12 to 36 hours, preferably about 24 hours. After the equilibration period, the alkyl cyanoacrylate is crystallized out of solution by gently agitating the container, such as by tapping the side of the container, or gently shaking the container. If the crystallization does not begin, the process is repeated every 15 minutes for 1 hour. If after an hour the alkyl cyanoacrylate still does not crystallize, a small piece of dry ice is placed against the outside of the container for about 30 seconds. Once the alkyl cyanoacrylate monomer begins to crystallize, the temperature of the container is increased by about 6xc2x0 C., preferably about 4xc2x0 C., most preferably about 2xc2x0 C. The crystallization process is allowed to sit undisturbed for about 24 to 72 hours, preferably about 48 hours. At the end of the crystallization period, the container is inverted so that the uncrystallized liquid in the container is drained into the reserve reservoir. The container is allowed to drain for about 30 minute or whatever time is required for the draining of the liquid to be completed. Once the draining is finished the valve between the container with the alkyl cyanoacrylate crystals and the reserve reservoir with the uncrystallized liquid is closed, separating the crystals from the liquid. The liquid is removed from the reserve reservoir and analyzed for the type and amount of impurities. Air is re-introduced into the container with the crystals. The container is also allowed to equilibrate to ambient room temperature, at which time the crystals melts. The melted crystals are analyzed for purity. The purified crystals of the alkyl cyanoacrylate monomer should be reformed into the stable composition of the present invention to prevent the monomer from polymerizing.
If the desired, the process is repeated in order to obtain the alkyl cyanoacrylate monomer at a desired purity. Generally, the process is repeated at least once to gain desired purity. Following purification, the crystalline alkyl cyanoacrylate should be re-formulated into the stable composition of the present invention to prevent the monomer from polymerizing.
The monomer component of the present invention comprises of at least one alkyl cyanoacrylate and at least one inhibitor agent. Typical inhibitors appropriate for cyanoacrylates are, for example, hydroquinone, p-methoxyphenol, pure phosphoric acid, and alkyl carboxylic acids, where the alkyl moiety ranges from 1 carbon, e.g., acetic acid, through to 15 and 17 carbons atoms in length, i.e., palmitic and stearic acids, respectively; and phosphoric acid at varying percentage solutions. Preferably hydroquinone, p-methoxyphenol, acetic acid and phosphoric acid are used, individually or in combination.
Different inhibitors have different physical characteristics and thereby functions to alter the final properties of the composition. For example, hydroquinone is primarily an inhibitor for high energy free radicals; p-methoxyphenol is primarily an inhibitor for low energy free radicals; and phosphoric acid acts to control or inhibit anionic polymerization and the rate of such polymerization.
The quantity of inhibitors used is measured in terms of parts per million of alkyl cyanoacrylate. For example, for 2-hexyl cyanoacrylate, hydroquinone is in the range of about 50 to 150 parts per million (PPM), p-methoxyphenol in the range of about 50 to 150 PPM, and phosphoric acid in the range of about 125 to 375 PPM, more preferred is hydroquinone in the range of about 75 to 125 PPM, p-methoxyphenol in the range of about 75 to 125 PPM, and phosphoric acid in the range of about 187.5 to 312.5 PPM, and most preferred is hydroquinone in the range of about 95 to 105 PPM, p-methoxyphenol in the range of about 95 to 105 PPM, and phosphoric acid in the range of about 200 to 300 PPM. Similarly, for a monomer component comprising of 90% n-hexyl cyanoacrylate and 10% methyl cyanoacrylate, hydroquinone is in the range of about 50 to 150 parts per million (PPM), p-methoxyphenol is in the range of about 50 to 150 PPM, and acetic acid is in the range of about 50 to 500 PPM, more preferred is hydroquinone in the range of about 75 to 125 PPM, p-methoxyphenol in the range of about 75 to 125 PPM and acetic acid in the range of about 100 to 300 PPM, and most preferred is hydroquinone in the range of about 95 to 105 PPM, p-methoxyphenol in the range of about 95 to 105 PPM, and acetic acid in the range of about 150 to 250 PPM.
The second component functions as an opacificant agent and a polymerization retardant. To this end, the second component can be an iodinated oil, such as Ethiodol, or a brominated oil. Typically the iodinated oil is mixed as some percent of the total volume of the final composition. The percentage solution of iodinated oil used will influence the polymerization rate and opacity of the composition. Generally advantageous ranges are from about 17% to 66%, preferably about 33%.
Alternatively, the second component can be a composition comprising, a opacificant material, such as gold, platinum, tantalum, titanium, tungsten and barium sulfate and the like; an alkyl cyanoacrylate polymer material, and an esterified fatty acid, where the fatty acids have 3 carbon atoms, for example, alkyl butyrate to 17 carbons, for example, alkyl stearate, preferred are, alkyl laurate, alkyl myristate, alkyl palmatate, and alkyl stearate, most preferred is alkyl myristate, and most especially preferred is ethyl myristate. The opacificant material is used in a fine powder form, typically, with individual particles sized no larger than about 7 microns in diameter, preferably about 5 microns, most preferred about 2 microns and most especially preferred is 1 micron or smaller.
The amount of opacificant material used relative to alkyl cyanoacrylate polymer will vary according to the specific materials. Factors that influence the determination of the ratio include the amount and size of the particles that are being coated by the alkyl cyanoacrylate polymer. For example, for 2-hexyl cyanoacrylate and gold, 2 g of 2-hexyl cyanoacrylate is used per 100 g of powdered gold (particle size of about 5xc2x12 microns) being coated. For example, for n-hexyl cyanoacrylate and gold, 2 mg of n-hexyl cyanoacrylate is used per 1 gm of gold at a particle size of about 2 to 10 xcexc, preferably about 0.1 to 1.0 xcexc, most preferably about 1 xc3x85. The amounts vary accordingly with the opacificant material being coated by the alkyl cyanoacrylate. The alkyl cyanoacrylate and opacificant material are mechanically mixed by processing the alkyl cyanoacrylate into small particulate masses, and mixing with the finely powdered opacificant material. The alkyl cyanoacrylate polymer coated material is then stored in an esterified fatty acid, which serves as a medium where the alkyl cyanoacrylate polymer coated material is maintained prior to use, and as a medium, which when contacted with the monomer component will not interfere with the polymerization of the composition. The unsealed storage containers, preferably appropriately sterilized bottles and caps or the like, with the cyanoacrylate polymer suspension is then treated with ethylene oxide, or alternatively ketene. This treatment should occur no later than about 48 hours after completion of the coating process, preferably within 24 hours. The treatment process provides sterilization and stabilization of the alkyl cyanoacrylate polymer coated material and follows standard procedures for ethylene oxide use, i.e., positioning the containers so that they are amply exposed to the gas for a sufficient period of time.
The characteristics of the composition of the invention can be modified for a specific application or environment in which the composition is intended to be utilized. For example, changes in the length and isomeric configuration of the alkyl side chains can alter the brittleness of a polymer formed from a cyanoacrylate monomer. Alkyl chains that result in the formation of smaller aggregates tend to be less brittle, while larger aggregates tend to be less flexible. Another method of modifying the characteristics of a polymer is to use a composition comprising of two or more types of alkyl cyanoacrylate monomers in combination with the appropriate inhibitors.
For example, a composition comprised of a monomer component comprising of 2-hexyl cyanoacrylate, hydroquinone, p-methoxyphenol and phosphoric acid; and a second component comprising of 2-hexyl cyanoacrylate polymer, gold, and ethyl myristate results in Polymer M. Alternatively, a composition comprised of a monomer component comprising of 90% n-hexyl cyanoacrylate and 10% methyl cyanoacrylate, hydroquinone, p-methoxyphenol and acetic acid; and a second component comprising of n-hexyl cyanoacrylate polymer, gold, and ethyl myristate, results in Polymer A.
A qualitative survey of Polymer M and A is shown in Table A. The physical characteristics disclosed are readily recognized by those of ordinary skill in the art as being relevant to the applications for which the polymers are used.
Polymers M and A have excellent cohesion properties. When introduced into a stationary fluid, or a fluid stream in motion, such as, the lumen of a blood vessel or other like passageway, the composition tend to stick together to itself remaining intact as a single mass or aggregate. This permits the polymers to be discretely deposited or placed at the desired location without the hazard of having potions of the composition breaking away and depositing at undesired locales. Polymers M and A appear to have viscosity properties that permit the injection of the liquid composition into a lumen of a blood vessel, duct, fistula or passageway in the body without using excessive pressure.
However, polymers M and A have different adhesion, polymerization and tactile properties. Polymer M is less adhesive than Polymer A, its polymerization profile upon contact with an anionic environment, such as, tissue or blood, is a transition from a liquid state to a semi-solid state before completing in a soft solid state, and the resultant polymer is a soft, rubbery, gummy solid. With these properties Polymer M is ideally suited for applications where the composition must penetrate further into anionic environment before arriving at the point of final placement. A preferred use is the treatment of arteriovenous malformations, also known as xe2x80x9cAVMxe2x80x9d. Polymer M is also ideally suited for the treatment of longer type urinary fistulas, this is because preferred treatment requires greater penetration into cavity space by the liquid composition. Additional applications suited for Polymer M are creating a tubal occlusion, and surgical adhesions. For example, a composition of the present invention is applied to raw intraperitoneal tissue to prevent the tissue from adhering to itself or other tissue.
Polymer A is more adhesive than M, its polymerization profile upon contact with an anionic environment, such as, tissue or blood, is a transition from a liquid state to a soft solid and completing as a firm solid. With these properties Polymer A is ideally suited for applications where the composition must quickly adhere and polymerize in the surrounding anionic environment. Particularly advantageous applications for Polymer A is treatment of various types of aneurysms.
Another advantageous application for Polymer A is the treatment of fistulas, particularly those where it is desirable to have the resultant aggregate structure form close to the point of deployment.
Still another advantageous use for Polymer A is for the maintenance of homeostasis during surgery, such as, during hepatectomy, renal surgery, and during gynecologic tumor surgery.
Further, Polymer A can be used to treat certain types of varicose veins, where Polymer A is injected into the portal vein.
The present invention is useful for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass (xe2x80x9ca spacexe2x80x9d). In particular, the composition is useful for filling an existing space, e.g., the lumen of a blood vessel, or the sac of an aneurysm, a space created by a transiently placed external device, e.g., a catheter or like device, a space created by a procedure, e.g., an excision or like procedure or implantation of an object, e.g., a stent or like device, or a space created by the composition; the composition is also useful for adhering tissue to tissue, or adhering tissue to a device. The composition has the property of polymerizing when it comes in contact with an anionic environment, or when it is deployed in situ in an existing space, e.g., the lumen of a blood vessel, or the sac of an aneurysm, a space created by a transiently placed external device, e.g., a catheter or like device, a space created by a procedure, e.g., an excision or like procedure or implantation of an object, e.g., a stent or like device, or a space created by the composition.
The present invention is useful as an embolic agent that selectively creates an embolic blockage in the lumen of a blood vessel, duct, fistula or other like body passageways.
The present invention can be prepared and maintained as a monomeric component and second component until needed. It has the ability to reliably and predictably change from a liquid state to a solid state, which is essential for its introduction and controlled placement into the lumen of vessel, duct, fistula or other like body passageways. The composition has low viscosity, which is essential for its administration by syringes and micro-catheters or other like devices.
The cohesive characteristics of the invention are such that when the composition in administered into an anionic fluid environment, such as blood, the composition forms a single aggregate structure. Additionally, the adhesive characteristics are such that the composition attaches to the lumen of vessel, duct, fistula or other like body passageways, but not to the degree where the device depositing the composition will become fixed to it before the practitioner can remove it.
The present invention causes mild tissue inflammation, sufficient to cause scarring, but not so severe to cause the formation of pus. Scar formation is desirable as the scar tissue is necessary to maintain the functionality of the embolic block after the composition has biodegraded, or otherwise eliminated from the lumen. The composition is sufficiently stable to biodegradation to allow for scarring to occur.
The present invention is radiopaque. Although this characteristic is not necessary for its function as an embolic agent, radiopacity allows the embolic block to be observed with x-ray or other such imaging techniques.
The rate of heat released during polymerization of the present invention is low enough such that the heat does not adversely effect surrounding tissues that may be heat sensitive, such as brain tissue.
The present invention and its biodegradation products are sufficiently non-histotoxic and non-cytotoxic so that its presence is well tolerated in the body.
The composition of the present invention is useful for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass (xe2x80x9ca spacexe2x80x9d).
The present invention provides a method for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass. The types of unfilled volumes or spaces within the scope of the present invention includes, but are not limited to the following instances.
For example, the present invention is used as a method of filling, occluding, partially filling or partially occluding an existing space, such as, a lumen of a passageway in the body, e.g., a blood vessel, a duct, an aneurysm, or a fistula. Examples of the types treatments covered by this method of use, include but are not limited to the following. The present invention is useful as a method of treating arteriovenous malformations (AVM) where the blood vessel(s) that feed the AVM are occluded thereby cutting off the blood supply to the AVM. The present invention is useful as a method to ablate diseased or undesired tissue by cutting off the tissue""s blood supply. In particular, the present invention is useful as a method of treating a tumor having a discrete blood supply, where the blood vessel(s) that feed the tumor are occluded thereby cutting off the blood supply to the tumor resulting in diminished growth or death of the tumor. The present invention is useful as a method of preventing or mitigating the development of an aneurysm by creating a partial occlusion at a location in the blood vessel selected to modify the fluid dynamics within the vessel to mitigate the formation or development of an aneurysm. The present invention is useful as a non-surgical method of treating symptomatic uterine leiomyomas by embolizing/occluding the uterine artery. This method has been reported using a non alkyl cyanoacrylate composition in the Journal of Vascular and Interventional Radiology, 10:891-894, July-August 1999. The present invention is useful as a method of sterilizing a female mammal by occluding the fallopian tubes thereby preventing the passage of the eggs from the ovaries to the uterus. The use of an occluding agent to sterilize a female mammal is disclosed in U.S. Pat. No. 5,989,580 xe2x80x9cMethod of Sterilizing Female Mammals,xe2x80x9d herein incorporated by reference. The methods disclosed in this patent can be advantageously applied using the compositions of the present invention, and are within the scope of the present invention.
The present invention is an embolic agent that provides a method for selectively creating and placing an embolic blockage which mechanically blocks, totally or partially, the lumen of a blood vessel, duct, fistula or other body passageway. In particular, the current invention is particularly useful in blocking, totally or partially, or diverting the flow of blood through the lumen.
The present invention can be advantageously used to block blood flow to certain tissues or areas. For example, the present invention can be used to treat arteriovenous malformation (AVM). An AVM is a collection of abnormal blood vessels which are neither arteries or veins. These vessels are packed closely together to form the nidus of the AVM. Blood flow into the AVM nidus is through thinned, enlarged, tortuous vessels and is rapidly shunted into draining veins because the nidus contains no arterioles or capillaries to provide high resistance. Clinical symptoms experienced because of AVMs are bleeding, re-direction of blood from nearby normal structures, or seizures. The primary clinical problem associated with cerebral AVM is the potential for lethal hemorrhage. The current standard of care for treating AVMs is surgical removal, high energy radiation or embolization with particular devices.
Further, the present invention can be used for treating cancer by diverting or blocking blood flow to tumors, the present invention is particularly useful for treating tumors in areas that are not easily accessible for surgical intervention, for example, brain tumors.
Other advantageous uses of the present invention are for aortopulmonary closure; treatment of artery pseudoaneursym; hepatic artery vascular occlusion and for temporary vascular occlusion during co-administration of cytotoxic drugs; treatment of other types of vessels, for example, the composition can be used for creating tubal occlusions, fallopian tube occlusions, vas deferens occlusions, and urinary occlusions.
The present invention provides a method of filling, occluding, partially filling or partially occluding a space created by a transiently placed external device, such as, a catheter balloon. Examples of the types of treatments covered by this method of use include, but are not limited to the following. The present invention is useful as a method of treating an aneurysm by filling the space within the aneurysm with a composition of the present invention, where the composition polymerizes in the space within the aneurysm, thereby preventing the rupture of the aneurysm. This treatment can be practiced using an administering means, comprising a means for stabilizing fluid flow distal or proximal to the body space being treated, and a means for delivering said composition to the desired body space. An embodiment of said administering means is where said means for stabilizing fluid flow distal or proximal to the body space being treated is in a first device, and said means for delivering said composition to the desired body space is in a second device. An embodiment of said first device comprises a temporary inflatable balloon, or like structure, that is inflated to stabilize fluid flow distal or proximal to the body space to be treated, and deflated for removal after some period after the composition has been delivered. Optionally said balloon structure may be juxtaposed adjacent to the body space where said composition is deposited, and inflated such that said balloon structure maintains said composition at the body space while the composition is polymerizing, and deflated for removal after some period after the composition has been delivered. An embodiment of the said second device comprises a catheter, or like device for delivering and depositing the composition of the present invention at a desired location. Another embodiment of said administering means is where said means for stabilizing fluid flow distal or proximal to the body space being treated, and said means for delivering said composition to the desired body space are within a single device or apparatus. Such apparatuses include, but are not limited to, catheters, catheter coils, catheter wires, catheter balloons, or like devices. Many examples of such devices are known to those of ordinary skill in the art. For example, U.S. Pat. No. 5,795,331 xe2x80x9cBalloon Catheter For Occluding Aneurysms of Branched Vesselsxe2x80x9d, incorporated herein by reference, discloses a device and methods for delivering compositions, such as those of the present invention. The device described combines an inflatable balloon with a catheter as a single apparatus, where the balloon is distal or proximal to the opening of the catheter. Embodiments of the described apparatus are commercially available from Micro Therapeutics, Inc., 2 Goodyear, Irvine, Calif. 92618, as a line of medical devices, such as, the Rebar(trademark) Micro Catheter, Equinox(trademark) Occlusion Balloon System and SilverSpeed(trademark) guidewires. Of additional note is that devices under the Rebar(trademark) Micro Catheter line have been approved by the U.S. Food and Drug Administration for use in treating conditions such as those within the present invention. U.S. Pat. No. 5,882,334 xe2x80x9cBalloon/Delivery Catheter Assembly With Adjustable Balloon Positioning,xe2x80x9d incorporated herein by reference, assigned to Target Therapeutics, San Jose, Calif., and U.S. Pat. No. 6,015,424 xe2x80x9cApparatus and Method For Vascular Embolizationxe2x80x9d, incorporated herein by reference, assigned to MicroVention, Inc., Aliso Viejo, Calif., describe like devices that can be employed in practicing the present invention. Additional commercial sources for like devices, include but are not limited to the following corporations, Guidant, Inc., Indianapolis, Ind.; Cook Incorporated, Bloomington, Ind.; Cordis, a subsidiary of Johnson and Johnson; and the SciMed, Target Therapeutics, and Medi-tech Divisions Boston Scientific Corporation. The present invention has been practiced following the procedure and utilizing like devices described in Neurosurgery, Vol. 31, No. 3, September 1992, page 591 xe2x80x9cCarotid-Cavernous Fistula Caused by a Ruptured Intra-cavernous Aneurysm: Endovascular Treatment by Electrothrombosis with Detailable Coils.xe2x80x9d The reference describes a procedure using a temporary inflatable balloon catheter, and a catheter for placement of a detachable platinum coil. A temporary balloon occlusion is performed proximally to a fistula, and then followed by the insertion of a platinum detachable coil into the fistula. The temporary balloon occlusion stabilizes the immediate environment near the fistula from the disturbed flow, increased flow, turbulence, or combination thereof created by normal unrestricted blood flow, while a thrombus forms around the platinum wire. In the present invention, a temporary balloon occlusion performs a similar function of stabilizing the immediate environment near the body space to be treated, for example, a fistula or aneurysm, from the disturbed flow, increased flow, turbulence, or combination thereof created by normal unrestricted blood flow. The temporary balloon, optionally, may also be used to temporarily form a seal at the opening of the body space, while the composition that had been deposited in the body space is polymerizing to its final form. After a period of time sufficient for the polymerization to be completed, the temporary balloon catheter is deflated and withdrawn.
The present invention also provides a method of filling, occluding, partially filling or partially occluding a space created or resulting from a procedure, such as with the excision of tissue, or insufflation. Examples of the types of treatments covered by this method of use include, but are not limited to the following. The present invention is useful as a method of treating oozing capillaries following an excision procedure.
The present invention further provides a method of filling, occluding, partially filling or partially occluding a space created by the placement or implantation of an object, such as, a medical device. Examples of the types of uses covered by this method of use include, but are not limited to the following. The present invention is useful as a method of restoring the normal fluid dynamics at the peripheral edges of a vascular stent by filling the dead spaces between the stent and the lumen wall created by the implantation of the stent.
Still another advantageous use is the controlling and smoothing the blood flow around stents. A major complication from the balloon angioplasty and the use of stents is disruption of the smooth flow of blood past and around the stent which can lead to the formation of blood clots and their associated complications. The composition of the present invention can be used to modify and make regular the slip streams of blood through and adjacent to the stent to mitigate or alleviate the cause of the turbulence, and such turbulence causing states.
The present invention further provides a method of filling, occluding, partially filling or partially occluding a space created by the composition itself, such as, where the composition is used as a bulking agent. Examples of the types of uses covered by this method of use include, but are not limited to the following. For example, a method of recreating normal external contours, such as following physical trauma.
The monomer component and second component of the present invention are combined just prior to use. The composition of the present invention is administered using any type of deployment device. The term xe2x80x9cdeployment devicexe2x80x9d refers to a device used to deploy fluids or compositions similar to those of the present invention, such as, a needle, catheter devices, catheter balloon, stereotaxic placement devices, or the like. Methods for using these devices are readily known to one of ordinary skill in the art, and such devices are commercially available. Such devices and methods are readily known to those of ordinary skill in art. For example in U.S. Pat. No. 5,925,683 xe2x80x9cLiquid Embolic Agentsxe2x80x9d, herein incorporated by reference, there is disclosed a method for introducing liquid embolic agents/solutions into the human body to form precipitated embolic occlusion masses, and also how this method is used for treating hepatic tumors using portal vein embolism. In U.S. Pat. No. 5,702,361 xe2x80x9cMethod for Embolizing Blood Vesselsxe2x80x9d, herein incorporated by reference, there is disclosed a method of embolizing a vascular site in a patient""s blood vessel comprising of introducing, via a catheter, at the vascular site to be emobolized a non-particulate agent or a plurality of such agents, and delivering, via a catheter, to said vascular site a polymer composition comprising a biocompatible polymer, a biocompatible solvent and contrast agent, wherein the delivery is conducted under conditions where the polymer precipitate forms in situ at the vascular site resulting in the embolizing of the blood vessel and where the non-particulate agent is encapsulated within the precipitate. An administrating means can be used to deliver the composition of the present invention to a desired location, said administering means comprising, a means for stabilizing fluid flow distal or proximal to the body space being treated, and a means for delivering said composition to the desired body space. An embodiment of said administering means is where said means for stabilizing fluid flow distal or proximal to the body space being treated is in a first device, and said means for delivering said composition to the desired body space is in a second device. An embodiment of said first device comprises a temporary inflatable balloon, or like structure, that is inflated to stabilize fluid flow distal or proximal to the body space to be treated, and deflated for removal after some period after the composition has been delivered. Optionally said balloon structure may be juxtaposed adjacent to the body space where said composition is deposited, and inflated such that said balloon structure maintains said composition at the body space while the composition is polymerizing, and deflated for removal after some period after the composition has been delivered. An embodiment of the said second device comprises a catheter, or like device for delivering and depositing the composition of the present invention at a desired location. Another embodiment of said administering means is where said means for stabilizing fluid flow distal or proximal to the body space being treated, and said means for delivering said composition to the desired body space are within a single device or apparatus. Such apparatuses include, but are not limited to, catheters, catheter coils, catheter wires, catheter balloons, or like devices. Many examples of such devices are known to those of ordinary skill in the art. For example, U.S. Pat. No. 5,795,331 xe2x80x9cBalloon Catheter For Occluding Aneurysms of Branched Vesselsxe2x80x9d, incorporated herein by reference, discloses a device and methods for delivering compositions, such as those of the present invention. The device described combines an inflatable balloon with a catheter as a single apparatus, where the balloon is distal to the opening of the catheter. Embodiments of the described apparatus are commercially available from Micro Therapeutics, Inc., 2 Goodyear, Irvine, Calif. 92618, as a line of medical devices, such as, the Rebar(trademark) Micro Catheter, Equinox(trademark) Occlusion Balloon System and SilverSpeed(trademark) guidewires. Of additional note is that devices under the Rebar(trademark) Micro Catheter line have been approved by the U.S. Food and Drug Administration for use in treating conditions such as those within the present invention. U.S. Pat. No. 5,882,334 xe2x80x9cBalloon/Delivery Catheter Assembly With Adjustable Balloon Positioning,xe2x80x9d incorporated herein by reference, assigned to Target Therapeutics, San Jose, Calif., and U.S. Pat. No. 6,015,424 xe2x80x9cApparatus and Method For Vascular Embolizationxe2x80x9d, incorporated herein by reference, assigned to MicroVention, Inc., Aliso Viejo, Calif., describe like devices that can be employed in practicing the present invention. Additional commercial sources for like devices, include but are not limited to the following corporations, Guidant, Inc., Indianapolis, Ind.; Cook Incorporated, Bloomington, Ind.; Cordis, a subsidiary of Johnson and Johnson; and the SciMed, Target Therapeutics, and Medi-tech Divisions Boston Scientific Corporation. The present invention has been practiced following the procedure and utilizing like devices described in Neurosurgery, Vol. 31, No. 3, September 1992, page 591 xe2x80x9cCarotid-Cavernous Fistula Caused by a Ruptured Intra-cavernous Aneurysm: Endovascular Treatment by Electrothrombosis with Detailable Coils.xe2x80x9d The reference describes a procedure using a temporary inflatable balloon catheter, and a catheter for placement of a detachable platinum coil. A temporary balloon occlusion is performed proximally to a fistula, and then followed by the insertion of a platinum detachable coil into the fistula. The temporary balloon occlusion stabilizes the immediate environment near the fistula from the disturbed flow, increased flow, turbulence, or combination thereof created by normal unrestricted blood flow, while a thrombus forms around the platinum wire. In the present invention, a temporary balloon occlusion performs a similar function of stabilizing the immediate environment near the body space to be treated, for example, a fistula or aneurysm, from the disturbed flow, increased flow, turbulence, or combination thereof created by normal unrestricted blood flow. The temporary balloon, optionally, may also be used to temporarily form a seal at the opening of the body space, while the composition that had been deposited in the body space is polymerizing to its final form. After a period of time sufficient for the polymerization to be completed, the temporary balloon catheter is deflated and withdrawn.
The composition of the present invention are administered with any type of commercially available needle, catheter devices, or stereotaxic placement devices, preferably in conjunction with imaging technology that provides the practitioner with guidance as to the placement of the composition. The compositions of the present invention can be used advantageously in conjunction with any embolization method that employs an embolizing agent, occluding agent, or such composition that creates an embolic block, or occlusion, or otherwise in effect is used for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass (xe2x80x9ca spacexe2x80x9d). Delivery can also be made with a micro catheter made from or coated with an agent that lessens the likelihood of accidental gluing of the device to the vessel, for example, hydrophilic coating and silicone derivative coatings.